Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition.

Based on the structure of signal transducer and activator of transcription 3 (STAT3), a series of 1,4-naphthoquinones derived from plumbagin (PL) with STAT3 inhibition potential were designed, synthesized, and biologically evaluated in vitro against several human cancer cell lines (MDA-MB-231, HepG2 and A549 cells) and three normal cells. The structure-activity relationship (SAR) and molecular docking result showed that the presence of hydroxyl group at C-5 of PL might interact with STAT3 in the form of hydrogen bonds, which is conducive to the binding of this kind structures with STAT3. Among the target compounds, 7a displayed the most potent inhibition against cancer cells and weaker cytotoxicity on normal cells than PL. The western bolting analysis showed that 7a could suppress the phosphorylation of STAT3 as well as the downstream genes instead of affecting its upstream tyrosine kinases (Src and JAK2) levels and p-STAT1 expression. Furthermore, molecular docking indicated that 7a bound to STAT3 more tightly than PL, and it could significantly induce the apoptosis of cancer cells in vitro. All these results may provide reference for the discovery of effective STAT3 inhibitors.

Novel anticancer hybrids from diazen-1-ium-1,2-diolate nitric oxide donor and ROS inducer plumbagin: Design, synthesis and biological evaluations.

High levels of both nitric oxide (NO) and reactive oxygen species (ROS) could act as pro-apoptotic signals in cancerous cells. In this study, we conjugated diazeniumdiolates (NONOates), an important class of NO donors, with a natural occurring plumbagin (PL) which is primarily an excellent ROS inducer. Herein, a total of 12 novel plumbagin/NONOate hybrids have been synthesized and evaluated for their inhibitory effects on a panel of human cancer cell lines (MDA-MB-231, A549, HepG2 and HCT-116 cells) and two normal human cells (HK-2 and WRL-68 cells). Among them, compounds 10a and 10b demonstrated superior potencies compared to their parent compound (IC50 values of 3.48-6.68 µM) against the above cancer cell lines but weak inhibitory effects on normal cells. In concordance with their selective cytotoxicities, 10a and 10b released higher level of NO in cancer cells than normal cells. Besides, the potent compound 10a induced apoptosis of A549 cells in a concentration-dependent manner and resulted in more ROS generation compared with the parent compound plumbagin.

Novel NO-releasing plumbagin derivatives: Design, synthesis and evaluation of antiproliferative activity.

A series of plumbagin/NO donor hybrids were designed, synthesized and evaluated in vitro against triple negative breast cancer (MDA-MB-231), hepatocellular (HepG2) and lung (A549) carcinoma cells. Most furoxan-based plumbagin derivatives exhibited significantly superior potency compared to their parent compound. Noticeably, MDA-MB-231 cells are the most sensitive to these furoxan-based plumbagin derivatives as evidenced by IC50 values ranging from 1.24 to 5.20 µM. Besides, NO released amounts detection of all hybrids suggested that in most cases, the antiproliferative activities were positively correlated with the levels of intracellular NO release in MDA-MB-231 cells. The most active compound (11a) also possessed higher chemical stability at different pHs (6.0, 7.4 and 8.0) than plumbagin. Together, the above promising results warrant the future potential of plumbagin/NO hybrids as the lead compounds against triple negative breast cancer deserving further research.